Cloutier Frank, Ongali Brice, Campos Maria M, Thibault Gaétan, Neugebauer Witold, Couture Réjean
Department of Physiology, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Québec, Canada H3C 3J7.
Br J Pharmacol. 2004 May;142(2):285-96. doi: 10.1038/sj.bjp.0705759. Epub 2004 Apr 5.
Intracerebroventricular (i.c.v.) effects of bradykinin (BK) B(1) and B(2) receptor agonists and antagonists were assessed on mean arterial blood pressure (MAP) and heart rate (HR) in awake unrestrained spontaneously hypertensive rats (SHR, aged of 8 and 16 weeks) and age-matched Wistar Kyoto rats (WKY). Quantitative in vitro autoradiographic studies were also performed on the brain of both strains with specific radioligands for B(2) receptors [(125)I]HPP-Hoe 140 and B(1) receptors [(125)I]HPP-des-Arg(10) and Hoe140. MAP increased linearly with doses of BK (81-8100 pmol) and the amplitudes were significantly greater in SHR, particularly at 16 weeks. While BK evoked a negative linear trend on HR (bradycardia) in WKY, a positive one (tachycardia) was observed in adult SHR. In both strains, BK-induced pressor response was blocked by equimolar doses of B(2) receptor antagonist, D-Arg-[Hyp(3), Thi(5), D-Tic(7), Oic(8)]-BK (Hoe 140), but not by B(1) receptor antagonist, AcLys[D-betaNal(7), Ile(8)]des-Arg(9)-BK (R-715). B(1) receptor agonists (Sar-[D-Phe(8)]-des-Arg(9)-BK, des-Arg(9)-BK, des-Arg(10)-Kallidin) and antagonist (R-715 alone or with Hoe 140) had no or marginal effect on MAP and HR at doses up to 8100 pmol in SHR and WKY. Higher densities of specific [(125)I]HPP-Hoe 140 labelling were found in discrete brain areas of SHR, especially in regions associated with cardiovascular function. Low levels of [(125)I]HPP-[des-Arg(10)]-Hoe140 binding sites were seen in WKY and SHR, yet densities were significantly greater in midbrain and cortical regions of SHR aged of 16 weeks. Contrary to SHR, ageing caused a downregulation of B(2) and B(1) receptor binding sites in specific brain nuclei in WKY. It is concluded that the hypersensitivity of the pressor response to i.c.v. BK in SHR occurs during both the early and established phases of hypertension in parallel with the enhancement of B(2) receptor binding sites in various cardiovascular brain centres. In contrast, brain B(1) receptors do not seem to participate in the central pressor effects of kinins nor in the maintenance of hypertension in SHR.
在清醒无束缚的自发性高血压大鼠（SHR，8周龄和16周龄）及年龄匹配的Wistar Kyoto大鼠（WKY）中，评估了缓激肽（BK）B(1)和B(2)受体激动剂及拮抗剂对平均动脉血压（MAP）和心率（HR）的脑室内（i.c.v.）作用。还使用B(2)受体特异性放射性配体[125I]HPP-Hoe 140和B(1)受体特异性放射性配体[125I]HPP-des-Arg(10)及Hoe140，对两种品系大鼠的脑进行了定量体外放射自显影研究。MAP随BK剂量（81 - 8100 pmol）呈线性增加，且在SHR中增幅显著更大，尤其是在16周龄时。虽然BK在WKY中引起HR呈负线性趋势（心动过缓），但在成年SHR中观察到正线性趋势（心动过速）。在两种品系中，BK诱导的升压反应均被等摩尔剂量的B(2)受体拮抗剂D-Arg-[Hyp(3), Thi(5), D-Tic(7), Oic(8)]-BK（Hoe 140）阻断，但未被B(1)受体拮抗剂AcLys[D-betaNal(7), Ile(8)]des-Arg(9)-BK（R-715）阻断。在SHR和WKY中，剂量高达8100 pmol时，B(1)受体激动剂（Sar-[D-Phe(8)]-des-Arg(9)-BK、des-Arg(9)-BK、des-Arg(10)-缓激肽原）和拮抗剂（单独使用R-715或与Hoe 140联合使用）对MAP和HR无影响或仅有轻微影响。在SHR的离散脑区发现了更高密度的特异性[125I]HPP-Hoe 140标记，尤其是在与心血管功能相关的区域。在WKY和SHR中均可见低水平的[125I]HPP-[des-Arg(10)]-Hoe140结合位点，但在16周龄SHR的中脑和皮质区域密度显著更高。与SHR相反，衰老导致WKY特定脑核中B(2)和B(1)受体结合位点下调。结论是，SHR对i.c.v. BK的升压反应超敏性在高血压的早期和确立阶段均会出现，同时伴随着各种心血管脑中枢中B(2)受体结合位点的增强。相比之下，脑B(1)受体似乎既不参与激肽的中枢升压作用，也不参与SHR高血压的维持。
